The idiopathic pulmonary fibrosis (IPF) belongs to those not so well understood diseases that keep clinicians and researchers worried: the often rapid progression of IPF is very distressing. Also the underlying causes are mostly unknown, pathophysiologic explanations and findings still unsatisfying. With only a 5-year survival rate of 20–40 %, only quick decisions such as initiating a lung transplantation, might help to prolong the patient’s life.

Definition of UIP

Usual interstitial pneumonia (UIP) is a chronic lung disease characterized by progressive scarring of both lungs. The fibrosis involves the interstitium of the lung and is therefore rated among the “interstitial lung diseases”.

In addition to the pathologic findings in the morphology of the lung, UIP may be of known or unknown cause and should be investigated for possible underlying clinical conditions such as asbestosis, autoimmune diseases, drug toxicity. In most cases the cause is unknown. The clinical term for UIP of unknown cause is idiopathic pulmonary fibrosis (IPF).

Image: “Figure A shows the location of the lungs and airways in the body. The inset image shows a detailed view of the lung’s airways and air sacs in cross-section. Figure B shows idiopathic pulmonary fibrosis (scarring) in the lungs. The inset image shows a detailed view of the fibrosis and how it damages the airways and air sacs.” by National Heart Lung and Blood Institute (NIH). License: Public Domain

Epidemiology of UIP and IPF

Spread of UIP and IPF

The epidemiology of UIP has been difficult to study because of its rarity and evolution in diagnostic and coding practices. Though uncommon, it is likely underappreciated both in terms of its occurrence (ie, incidence, prevalence) and public health impact (ie, health care costs and resource utilization). Of the over 150 recognized types of interstitial lung disease (ILD) in pulmonology practices, IPF is the most common with an estimated prevalence of 50 per 100,000.

IPF prevalence and incidence increase with age, are higher among males and appear to be on the increase in recent years. The disease occurs primarily in middle-aged and older adults.

Etiology of UIP and IPF

Causes of UIP and IPF

The etiology of idiopathic pulmonary fibrosis remains undefined. However, in the current hypothesis regarding the pathogenesis of idiopathic pulmonary fibrosis (IPF), exposure to an inciting agent like smoke, environmental pollutants, environmental dust, viral infections, gastroesophageal reflux disease or chronic aspiration in a vulnerable host may lead to the initial alveolar epithelial injury.

It has been hypothesized that no single etiologic agent serves as a common inciting event but rather that affected patients might have common defects in reparative pathways (ie, abnormal wound healing).

Cigarette smoking is the best recognized and most accepted risk factor for IPF, and increases the risk of IPF by about twofold. And because one type of idiopathic pulmonary fibrosis runs in families, heredity also is thought to play a role.

Pathology and Pathophysiology of UIP and IPF

There are four key features of UIP including interstitial fibrosis in a ‘patchwork pattern’, interstitial scarring, honeycomb changes and fibroblast foci. Fibroblastic foci are dense collections of myofibroblasts and scar tissue and, together with honeycombing, are the main pathological findings that allow a diagnosis of UIP.

Lung tissue from people with IPF usually shows a characteristic histopathologic UIP pattern and is therefore the pathologic counterpart of IPF.

Image: “Honeycomb change on a surgical lung biopsy.” by Mutleysmith. License: Public Domain

The gross appearance of the lungs in IPF shows a characteristic fibrosis that is distributed along the inferior portions of the lobes with subpleural accentuation. The pleural surface has a bosselated or cobblestone appearance, and on cut section, these regions correspond to areas of airspace enlargement and fibrotic retraction. This pattern of fibrosis has been termed gross honeycombing. The typical microscopic appearance of IPF has been termed usual interstitial pneumonia.

Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease.

The process to replace damaged epithelium after an injury with a new one, plays an important role in physiological wound healing.

Image: “Fibroblast focus in UIP” by Mutleysmith. License: Public Domain

However the current theory for the development of an idiopathic pulmonary fibrosis says, that such injuries or damages to the alveolar epithelial cells can lead to an exaggerated activation of mesenchymal cells. Those proliferate and form fibroblastic foci. Fibroblasts and myofibroblasts accumulate and lead to the irreversible fibrosis.

Symptoms of UIP and IPF

Signs of UIP and IPF

The clinical symptoms of idiopathic pulmonary fibrosis are nonspecific. Most patients present with exertional dyspnea and a nonproductive cough. Such symptoms can be shared with a variety of pulmonary and cardiac diseases. Dyspnea, which is the most prominent symptom in IPF, usually begins insidiously and is often progressive. Associated systemic symptoms can occur but are not common. Some of these systemic symptoms include weight loss, low-grade fevers, fatigue, arthralgias or myalgias.

The symptoms of IPF develop over time and may not even begin to appear until the disease has done serious damage to the lungs. The course of pulmonary fibrosis and the severity of symptoms can vary considerably from person to person.

Diagnostics of UIP and IPF

History and physical findings

It is critical to obtain a complete history, including medication history, drug use, social history, occupational, recreational, and environmental respiratory exposure history, risk factors for human immunodeficiency virus infection and review of systems, to ensure other causes of interstitial lung disease are excluded. Amiodarone, bleomycin, and nitrofurantoin are notable medications associated with pulmonary fibrosis.

Dry, inspiratory bibasilar velcro-like crackles would be heard on auscultation. Assessment of velcro crackles on lung auscultation is a practical way to improve the earlier diagnosis of IPF. Fine crackles are easily recognized by clinicians and are characteristic of IPF. Many patients show a pulmonary hypertension while being at rest. Then a split second heart sound might be found on auscultation, as well as a dominant P2 component of S2.Digital clubbing is seen in 30–50 % of patients with idiopathic pulmonary fibrosis (IPF) and should be observed while examining the patient.

Cyanosis and peripheral edema may be observed in the late phases of the disease.

Physicians should pay attention to historical clues that may suggest the presence of obstructive sleep apnea (OSA) because studies have demonstrated the high prevalence of OSA in patients with idiopathic pulmonary fibrosis.

Pulmonary function tests

The typical findings on pulmonary function tests in patients with idiopathic pulmonary fibrosis are a restrictive ventilatory defect and a reduced diffusion capacity for carbon monoxide.

Measurement of static lung volumes using body plethysmography typically reveals reduced lung volumes (restriction). Vital capacity, functional residual capacity, total lung capacity, and forced vital capacity (FVC) all are reduced. Additionally, the static pressure-volume curve is shifted downward and to the right as a result of decreased lung compliance.

Diagnostic Imaging

HRCT Scans

The radiological evaluation through high-resolution computed tomography (HRCT) is an essential point in the diagnostic pathway in IPF as HRCT findings are significantly more sensitive and specific for the diagnosis.

On HRCT images, idiopathic pulmonary fibrosis is characterized by patchy, peripheral, subpleural and bibasilar reticular opacities. Typical HRCT of the chest of IPF demonstrates fibrotic changes in both lungs, with a predilection for the bases and the periphery.

Many patients with IPF have an abnormal chest radiograph at the time of diagnosis. The typical findings are peripheral reticular opacities (netlike linear and curvilinear densities) predominantly at the lung bases. Honeycombing (coarse reticular pattern) and lower lobe volume loss can also be seen.

Procedures

A surgical lung biopsy specimen obtained video-assisted thoracoscopic surgery (VATS) provides the best sample for which to distinguish usual interstitial pneumonia from other idiopathic interstitial pneumonias.

Bronchoscopy with BAL

Bronchoscopy with Bronchoalveolar Lavage (BAL) and/or transbronchial biopsy is a well-tolerated diagnostic procedure in tool in idiopathic pulmonary fibrosis. In the evaluation of patients with suspected IPF, the most important application of BAL is in the exclusion of other diagnoses.

Therapy of UIP and IPF

Treatment of UIP and IPF

The goals of treatment in IPF are essentially to reduce the symptoms, stop disease progression, prevent acute exacerbations and prolong survival. Any underlying conditions that might help the disease to progress should be treated (for example gastroesophageal reflux disease, obstructive sleep apnea, nicotin abusus and side effects caused by medicaments).

Pharmacologic therapy

N-acetylcysteine (NAC)

Treatment with high doses of NAC may repair an oxidant–antioxidant imbalance that occurs in the lung tissue of patients with IPF. In addition, NAC reduced the decline in VC and DLCO over 12 months of follow-up when used in combination with prednisolone and azathioprine (triple therapy).

However, in 2011, a guideline for the treatment of idiopathic pulmonary fibrosis (composed and validated by an international group of leading respiratory societies) mentions a “conditional recommendation against the use of N-acetylcysteine monotherapy”.

Our systematic review of the available evidence on IPF treatments points to the need for additional research and long-term studies of their safety and efficacy, Ganesh Raghu, member of the committee, explained and further:

The guidelines empower the clinician to make the most appropriate treatment choices for the patient confronted with IPF and encourage shared decision-making with the well informed patient to choose the most appropriate treatment options tailored to the individual patient’s needs.

Antifibrotic agents

Pirfenidone is an anti-fibrotic drug for the treatment of IPF. It works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II. Pirfenidone improved progression-free survival and, to a lesser effect, pulmonary function in patients with IPF.

Angiokinase inhibitors

Nintedanib inhibits multiple tyrosine kinases and targets growth factors, which have been shown to be potentially involved in pulmonary fibrosis.

Non-pharmacologic therapy

Long term oxygen therapy

Oxygen therapy or supplementary oxygen for home use, is a strong recommendation for use in those patients with clinically significant resting hypoxemia.

Respiratory rehabilitation

Pulmonary rehabilitation could alleviate the overt symptoms of IPF and improve functional status by stabilizing and/or reversing the extrapulmonary features of the disease. Respiratory rehabilitation programs may include exercise training, smoking cessation, psychosocial assistance and supportive care.

Lung transplantation

Lung transplantation for idiopathic pulmonary fibrosis has been shown to confer a survival benefit over medical therapy. The most recent data suggest that bilateral lung transplantation is superior to single lung transplantation in patients with IPF

Palliative care

Palliative care focuses on reducing symptoms and improving the comfort of patients rather than treating the disease.

Progression and Prognosis of UIP and IPF

IPF progression is associated with an estimated median survival time of 2 to 5 years following diagnosis. The 5-year survival for IPF ranges between 20–40 %. In IPF patients, the overall mortality at 5 years rate is high but the annual rate of all-cause mortality in patients with mild to moderate lung impairment is relatively low. Respiratory failure resulting from disease progression is the most frequent cause of death.

Patients with IPF may suffer periods of acute respiratory decline either due to known complications, such as infection or of unknown cause (acute exacerbation of IPF). The rate of decline and progression to death in patients with IPF may take several clinical forms: slow physiologic deterioration with worsening severity of dyspnea, rapid deterioration and progression to death, or periods of relative stability interposed with periods of acute respiratory decline sometimes manifested by hospitalizations for respiratory failure.

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